Compounds for the treatment of metabolic disorders

ABSTRACT

Agents useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyper-lipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis are disclosed. Formula (I) wherein n is 1 or 2; m is 0 to 4; q is 0 or 1; t is 0 or 1; R 2  is alkyl having from 1 to 3 carbon atoms; R 3  is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalendy bound to the remainder of the compound of formula (I) by a ring carbon; and R 1  is hydrogen or alkyl having 1 or 2 carbon atoms. Alternatively, when R 1  is hydrogen, the biologically active agent can be a pharmaceutically acceptable salt of the compound of Formula (I).

BACKGROUND OF THE INVENTION

Diabetes mellitus is a major cause of morbidity and mortality.Chronically elevated blood glucose leads to debilitating complications:nephropathy, often necessitating dialysis or renal transplant;peripheral neuropathy; retinopathy leading to blindness; ulceration ofthe legs and feet, leading to amputation; fatty liver disease, sometimesprogressing to cirrhosis; and vulnerability to coronary artery diseaseand myocardial infarction.

There are two primary types of diabetes. Type I, or insulin-dependentdiabetes merfitus (IDDM) is due to autoimmlune destruction ofinsulin-producing beta cells in the pancreatic islets. The onset of thisdisease is usually in childhood or adolescence. Treatment consistsprimarily of multiple daily injections of insulin, combined withfrequent testing of blood glucose levels to guide adjustment of insulindoses, because excess insulin can cause hypoglycemia and consequentimpairment of brain and other functions.

Type II, or noninsulin-dependent diabetes meritus (NDDM) typicallydevelops in adulthood. NIDDM is associated with resistance ofglucose-utilizing tissues like adipose tissue, muscle, and liver, to theactions of insulin. Initially, the pancreatic islet beta cellscompensate by secreting excess insulin. Eventual islet failure resultsin decompensation and chronic hyperglycemia. Conversely, moderate isletinsufficiency can precede or coincide with peripheral insulinresistance. There are several classes of drugs that are useful fortreatment of NIDDM: 1) insulin releasers, which directly stimulateinsulin release, carrying the risk of hypoglycemia; 2) prandial insulinreleasers, which potentiate glucose-induced insulin secretion, and mustbe taken before each meal; 3) biguanides, including metformin, whichattenuate hepatic gluconeogenesis (which is paradoxically elevated indiabetes); 4) insulin sensitizers, for example the thiazolidinedionederivatives rosiglitazone and pioglitazone, which improve peripheralresponsiveness to insulin, but which have side effects like weight gain,edema, and occasional liver toxicity; 5) insulin injections, which areoften necessary in the later stages of NIDDM when the islets have failedunder chronic hyperstimulation.

Insulin resistance can also occur without marked hyperglycemia, and isgenerally associated with atherosclerosis, obesity, hyperlipidemia, andessential hypertension. This cluster of abnormalities constitutes the“metabolic syndrome” or “insulin resistance syndrome”. Insulinresistance is also associated with fatty liver, which can progress tochronic inflammation (NASH; “nonalcoholic steatohepatitis”), fibrosis,and cirrhosis. Cumulatively, insulin resistance syndromes, including butnot limited to diabetes, underlie many of the major causes of morbidityand death of people over age 40.

Despite the existence of such drugs, diabetes remains a major andgrowing public health problem. Late stage complications of diabetesconsume a large proportion of national health care resources. There is aneed for new orally active therapeutic agents which effectively addressthe primary defects of insulin resistance and islet failure with feweror milder side effects than existing drugs.

Currently there are no safe and effective treatments for fatty liverdisease. Therefore such a treatment would be of value in treating thiscondition.

WO 02/100341 (Wellstat Therapeutics Corp.) discloses4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid. WO 02/100341 doesnot disclose any compounds within the scope of Formula I shown below, inwhich on the oxo-acid moiety the two oxo groups are immediately adjacentto one another.

SUMMARY OF THE INVENTION

This invention provides a biologically active agent as described below.This invention provides the use of the biologically active agentdescribed below in the manufacture of a medicament for the treatment ofinsulin resistance syndrome, diabetes, cachexia, hyperlipidemia, fattyliver disease, obesity, atherosclerosis or arteriosclerosis. Thisinvention provides methods of treating a mammalian subject with insulinresistance syndrome, diabetes, cachexia, hyperlipidemia, fatty liverdisease, obesity, atherosclerosis or arteriosclerosis comprisingadministering to the subject an effective amount of the biologicallyactive agent described below. This invention provides a pharmaceuticalcomposition comprising the biologically active agent described below anda pharmaceutically acceptable carrier.

The biologically active agent in accordance with this invention is acompound of Formula I:

wherein n is 1 or 2; m is 0, 1, 2, 3 or 4; q is 0 or 1; t is 0 or 1; R²is alkyl having from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkylhaving from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbonatoms;

A is phenyl, unsubstituted or substituted by 1 or 2 groups selectedfrom: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxyhaving 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl havingfrom 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted orone or two ring carbons are independently mono-substituted by methyl orethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ringheteroatoms selected from N, S and O and the heteroaromatic ring iscovalently bound to the remainder of the compound of formula I by a ringcarbon; and R¹ is hydrogen or alkyl having 1 or 2 carbon atoms.Alternatively, when R¹ is hydrogen, the biologically active agent can bea pharmaceutically acceptable salt of the compound of Formula I.

The biologically active agents described above have activity in one ormore of the biological activity assays described below, which areestablished animal models of human diabetes and insulin resistancesyndrome. Therefore such agents would be useful in the treatment ofdiabetes and insulin resistance syndrome. All of the exemplifiedcompounds that were tested demonstrated activity in at least one of thebiological activity assays in which they were tested.

DETAILED DESCRIPTION OF THE INVENTION

Definions

As used herein the term “alkyl” means a linear or branched-chain alkylgroup. An alkyl group identified as having a certain number of carbonatoms means any alkyl group having the specified number of carbons. Forexample, an alkyl having three carbon atoms can be propyl or isopropyl;and alkyl having four carbon atoms can be n-butyl, 1-methylpropyl,2-methylpropyl or t-butyl.

As used herein the term “halo” refers to one or more of fluoro, chloro,bromo, and iodo.

As used herein the term “perfluoro” as in perfluoromethyl orperfluoromethoxy, means that the group in question has fluorine atoms inplace of all of the hydrogen atoms.

As used herein “Ac” refers to the group CH₃C(O)—.

Certain chemical compounds are referred to herein by their chemical nameor by the two-letter code shown below. Compound CQ is included withinthe scope of Formula I shown above.

-   BI 4-(3-(2,6-Dimethylbenzyloxy)phenyl)4-oxobutyric acid-   CF 3-(2,6-Dimethylbenzyloxy)phenylacetic acid-   CG 3-(2,6-Dimethylbenzyloxy)benzoic acid-   CQ [3-(2,6-Dimethylbenzyloxy)-phenyl]-oxoacetic acid

As used herein the transitional term “comprising” is open-ended. A claimutilizing this term can contain elements in addition to those recited insuch claim.

Compounds of the Invention

In an embodiment of the agent, use, method or pharmaceutical compositionof this invention, n is 1; q is 0; t is 0; R³ is hydrogen; and A isphenyl, unsubstituted or substituted by 1 or 2 groups selected from:halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy. In a more specific embodiment,A is 2,6-dimethylphenyl. Examples of such compounds include Compound CQ.

In a preferred embodiment of the biologically active agent of thisinvention, the agent is in substantially (at least 98%) pure form.

Reaction Schemes

The biologically active agents of the present invention can be made inaccordance with the following reaction schemes.

The compound of formula I where m is 0, q is 0, t is 0 or 1, and n is 1or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atoms oralkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen or alkylhaving from 1 to 2 carbon atoms, R² is alkyl having from 1 to 3 carbonatoms i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme1.

In the reaction scheme of Scheme 1, A, t, n, R³ and R¹ are as above. Yis a leaving group. The compound of formula II is converted to thecompound of formula V via reaction of step (a) using Mitsunobucondensation of II with III using triphenylphosphine and diethylazodicarboxylate or diisopropyl azodicarboxylate. The reaction iscarried out in a suitable solvent for example tetrahydrofuran. Any ofthe conditions conventionally used in Mitsunobu reactions can beutilized to carry out the reaction of step (a).

The compound of formula V can also be prepared by etherifying oralkylating the compound of formula II with a compound of formula IV viathe reaction of step (b) by using suitable base such as potassiumcarbonate, sodium hydride, triethylamine, pyridine and the like. In thecompound of formula IV, Y, include but are not limited to mesyloxy,tosyloxy, chloro, bromo, iodo, and the like. Any conventional conditionsto alkylate a hydroxyl group with a leaving group can be utilized tocarry out the reaction of step (b). The reaction of step (b) ispreferred over step (a) if compound of formula IV is readily available.

The compound of formula V can be converted to the compound of formulaVII via reaction of step (c) by oxidation of methyl group with seleniumdioxide (VI) in the presence of pyridine. Generally the reaction iscarried out at temperatures of from 25° C.-100° C. The product can beisolated and purified by techniques such as extraction, evaporation,chromatography, and recrystallization.

The compound of formula VII is the compound of formula I where m is 0and R¹ is H.

The compound of formula VII can be converted to compound of formula Iwhere R¹ is alkyl having from 1 to 2 carbon atoms by esterificationusing C₁-C₂ alkyl chloroformate. The reaction can be carried out byusing base for example triethylamine and the like. Generally thereaction is carried out in solvent such as ethyl acetate or the like.Generally the reaction is carried out at temperatures of from 0° C. to25° C. The product can be isolated and purified by techniques such asextraction, evaporation, chromatography, and recrystallization.

The compound of formula I where m is 0, q is 1, t is 0 or 1, and n is 1or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atoms oralkyl having from 1 to 3 carbon atoms, R² is alkyl having from 1 to 3carbon atoms and R¹ is hydrogen or alkyl having from 1 to 2 carbonatoms, i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme2.

In the reaction scheme of Scheme 2, A, t, n, R³and R² are as above. Y ischloro or bromo. The compound of formula IX can be mesylated to furnishthe compound of formula X via reaction of step (e). Any conventionalconditions to carry out the mesylation reaction of a hydroxyl group canbe utilized to carry out the step (e). The compound of formula X is thenheated with the compound of formula XI to produce the compound offormula XII. Any of the conditions conventional to produce amino alcoholcan be utilized to carry out the reaction of step (f).

In the compound of formula XII, alcohol can be displaced by chloro orbromo by treating the compound of formula XII with thionyl chloride,bromine, phosphorus tribromide and the like to produce the compound offormula XIII. Any conventional method to displace alcohol with chloro orbromo can be utilized to carry out the reaction of step (g).

The compound of formula XIII can be reacted with the compound of formulaII via reaction of step (h) in the presence of a suitable base such aspotassium carbonate, sodium hydride, triethylamine and the like. Thereaction is carried out in conventional solvents such asdimethylformamide, tetrahydrofuran and the like to produce thecorresponding compound of formula XIV. Any conventional method ofetherification of a hydroxyl group in the presence of base (preferredbase being potassium carbonate) can be utilized to carry out thereaction of step (h).

The compound of formula XIV can be converted to the compound of formulaXV via reaction of step (i) by oxidation of methyl group with seleniumdioxide (VI) in the presence of pyridine. Generally the reaction iscarried out at temperatures of from 25° C.-100° C. The product can beisolated and purified by techniques such as extraction, evaporation,chromatography, and recrystallization.

The compound of formula XV is the compound of formula I where m is 0 andR¹ is H.

The compound of formula XV can be converted to compound of formula Iwhere R¹ is alkyl having from 1 to 2 carbon atoms by esterificationusing C₁-C₂ alkyl chloroformate. The reaction can be carried out byusing base for example triethylamine and the like. Generally thereaction is carried out in solvent such as ethyl acetate or the like.Generally the reaction is carried out at temperatures of from 0° C. to25° C. The product can be isolated and purified by techniques such asextraction, evaporation, chromatography, and recrystallization.

The compound of formula I where m is 1, q is 0 or 1, t is 0 or 1, and nis 1 or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atomsor alkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen or alkylhaving from 1 to 2 carbon atoms, R² is alkyl having from 1 to 3 carbonatoms i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme3.

In the reaction of Scheme 3, t, n, A, R², R³ and R¹ are as above. Y ischloro or bromo. The compound of formula XVII can be converted to thecompound of formula XVIII via reaction of step (k) by reaction withcompound of formula III or the compound of formula IV (prepared in thesame manner as described in the reaction of scheme 1) or with thecompound of formula XIII (prepared in the same manner as described inthe reaction of scheme 2). These reactions can be carried out in thesame manner as described in connection with reaction steps of (a), (b)or (h).

The compound of formula XVIII can be converted to the compound offormula XIX via reaction of step (1) by reaction with hydantoin in thepresence of base for example piperidine. The compound of formula XIX canbe converted to the compound of formula XX via reaction of step (m) bytreatment with aqueous sodium hydroxide. The compound of formula XX canbe converted to the compound of formula XXI via reaction of step (n) bytreatment with acid. (Method Adapted from Organic Syntheses; Wiley: NewYork, 1973; Collect. Vol. 5 p. 627).

The compound of formula XXI is the compound of formula I where m is 1and R¹ is H.

The compound of formula XXI can be converted to compound of formula Iwhere R¹ is alkyl having from 1 to 2 carbon atoms by esterificationusing C₁-C₂ alkyl chloroformate. The reaction can be carried out byusing base for example triethylamine and the like. Generally thereaction is carried out in solvent such as ethyl acetate or the like.Generally the reaction is carried out at temperatures of from 0° C. to25° C. The product can be isolated and purified by techniques such asextraction, evaporation, chromatography, and recrystallization.

In the other method, the compound of formula XVIII can be reacted withthe compound of formula XXII in the presence of acetic anhydride andsodium acetate via reaction of step (o) to give the compound of formulaXXIII. The compound of formula XXIII can be hydrolyzed by aqueous acidto give the compound of formula XXIV as described in Synthesis, 1992,793 and J. Org. Cher. 1956, 21, 1149.

The compound of formula XXIV is the compound of formula I where m is 1and R¹ is H.

The compound of formula XXIV can be converted to compound of formula Iwhere R¹ is alkyl having from 1 to 2 carbon atoms by esterificationusing C₁-C₂ alkyl chloroformate. The reaction can be carried out byusing base for example triethylamine and the like. Generally thereaction is carried out in solvent such as ethyl acetate or the like.Generally the reaction is carried out at temperatures of from 0° C. to25° C. The product can be isolated and purified by techniques such asextraction, evaporation, chromatography, and recrystalalation.

The compound of formula I, where m is 1 and q is 0 or 1, can besynthesized from the compound of formula XXV:

wherein A is described as above, R⁴ is alkyl group having from 1 to 2carbon atoms via reaction of scheme 4.

In the reaction of scheme 4, t, n, A, R², R³, R⁴ and R¹ are ashereinbefore defined. Y is halo.

The compound of formula XXV can be converted to the compound of formulaXXVI via reaction of step (q) by reaction with compound of formula IIIor with the compound of formula IV (prepared in the same manner asdescribed in the reaction of scheme 1) or with the compound of formulaXIII (prepared in the same manner as described in the reaction of scheme2). These reactions can be carried out in the same manner as describedin connection with reaction steps of (a), (b) or (h).

The compound of formula XXVI can be hydrolyzed via reaction of step (r)to produce acid, which was then subsequently reduced via reaction ofstep (s) to give alcohol of formula XXVII. The reaction can be carriedout by utilizing a conventional reducing agent that converts acid toalcohol. In carrying out this reaction it is generally preferred but notlimited to utiiie lithium alumnnium hydride as the reducing agent.Generally this reaction is carried out in solvents such astetrahydrofuran. Generally the reaction is carried out at temperaturesof from 0° C. to 25° C. The product can be isolated and purified bytechniques such as extraction, evaporation, chromatography, andrecrystalltion.

In the compound of formula XXVII, hydroxyl group can be displaced bychloro or bromo via reaction of step (t). The compound of formula XXVIIcan be treated with thionyl chloride, bromine, phosphorus tribromide andthe like to produce the compound of formula XXVIII. Any conventionalmethod to displace alcohol with chloro or bromo can be utilized to carryout the reaction of step (t).

The compound of formula XXVIII can be converted to the compound offormula XXIX via reaction of step (u) by carbonylating with CO inorganic solvent and base in the presence of metal cluster catalyst forexample Co carbonyls (JP 62116541), [C₆H₅CH₂(CH₃)₃N]⁺[FeCo₃(CO)₁₂]⁻(CN1125217), Co pyridine-2-carboxylate (CN 1279233) and the like.

The compound of formula XXIX is the compound of formula I where m is 1and R¹ is H.

The compound of formula XXIX can be converted to the compound of formulaI where R¹ is alkyl having from 1 to 2 carbon atoms by esterificationusing C₁-C₂ alkyl chloroformate. The reaction can be carried out byusing base for example triethylamine and the like. Generally thereaction is carried out in solvent such as ethyl acetate or the like.Generally the reaction is carried out at temperatures of from 0° C. to25° C. The product can be isolated and purified by techniques such asextraction, evaporation, chromatography, and recrystallization.

The compound of formula I where m is 2, q is 0 or 1, t is 0 or 1, and nis 1 or 2, R³ is hydrogen, halo, alikoxy having from 1 to 3 carbon atomsor alkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen or alkylhaving from 1 to 2 carbon atoms, R² is alkyl having from 1 to 3 carbonatoms i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme5.

In the reaction of scheme 5, t, n, A, R², R³ and R¹ are as hereinbeforedefined. The compound of formula XXXIII can be synthesized by adaptingmethod from EP 387058.

The compound of formula XVIII (synthesized in the same manner asdescribed in the connection with reaction of steps (k) in scheme 3) canbe reacted with the compound of formula XXX in the presence of base togive the compound of formula XXXI. The compound of formula XXXI can beesterified via reaction of step (w) by treating the acid with a C₁-C₂alkyl chloroformate. The reaction can be carried out by using base forexample triethylamine and the like. Generally the reaction is carriedout in solvent such as ethyl acetate or the like. Generally the reactionis carried out at temperatures of from 0° C. to 25° C. The product canbe isolated and purified by techniques such as extraction, evaporation,chromatography, and recrystzlization.

The compound of formula XXXII can be reduced by using heterogeneouscatalyst such as PdCl₂/NaBH₄ in the presence of hydrogen to givecompound of formula XXXIII via reaction of step (x).

The compound XXXIII is the compound of formula I where m is 2 and R¹ isalkyl having from 1 to 2 carbon atoms. The compound of formula XXXIIIcan be converted to the compound of formula I where R¹ is H by esterhydrolysis.

The compound of formula I where m is 3 to 4, q is 0 or 1, t is 0 or 1,and n is 1 or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbonatoms or alkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen oralkyl having from 1 to 2 carbon atoms, R² is alkyl having from 1 to 3carbon atoms i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme6.

In the reaction of scheme 6, t, n, A, R², and R³ are as hereinbeforedefined. R¹ is alkyl having from 1 to 2 carbon atoms and p is 3 or 4.

The compound of formula XXXIX can be synthesized by adapting method fromJ. Org. Chem., Vol. 37, No. 3, 1972, 505-506.

The compound of formula XXXIV can be reacted with the compound offormula XXXV via reaction of step (y) to give compound of formula XXXVI.The reaction can be done using nonaqueous conditions by treatment withboron trifluoroetherate in chloroform Any of the conditions conventionalfor these reactions can be utilized to carry out the reaction of step(y).

The compound of formula XXXVI can be alkylated by the compound offormula XXXVII via reaction of step (z) to give the compound of formulaXXXVIII. The reaction can be carried out by utilizing a conventionalbase for example sodium hydride and the like. Generally this reaction iscarried out in solvents such as N, N-Dimethylformamide-benzene. Theproduct can be isolated and purified by techniques such as extraction,evaporation, chromatography, and recrystallization.

The compound of formula XXXVIII can be converted to the compound offormula XXXIX via reaction of step (a′) by using method as described inSynthesis, 1, 17 (1969).

The compound XXXIX is the compound of formula I where R¹ is alkyl havingfrom 1 to 2 carbon atoms. The compound of formula XXXIX can be convertedto the compound of formula I where R¹ is H by ester hydrolysis.

The compound of formula XXXVII where q is 0 or 1, t is 0 or 1, and n is1 or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atoms oralkyl having from 1 to 3 carbon atoms, and R² is alkyl having from 1 to3 carbon atoms i.e. compounds of formula:

wherein A is described as above, and p is 3 to 4 can be prepared viareaction of scheme 7.

In the reaction of scheme 7, t, n, A, R², and R³ are as hereinbeforedefined. R¹ is alkyl having from 1 to 2 carbon atoms and k is 1 to 2. R⁴is alkyl group having from 1 to 2 carbon atoms and s is 0 to 1.

The compound of formula XVIII (synthesized in the same manner asdescribed in the reaction scheme 3 via reaction of step (k)) can beconverted to the compound of formula XLI via reaction of step (b′) usingWittig reaction by treating the compound of formula XVIII with thecompound of formula XL. Any conventional method of reacting an aldehydewith triarylphosphine hydrohalide can be uilized to carry out thereaction of step (b′). Any of the conditions conventional in Wittigreactions can be utilizd to carry out the reaction of step (b′). Theproduct can be isolated and purified by techniques such as extraction,evaporation, chromatography, and recrystallization.

The compound of formula XLI can be converted to the compound of formulaXLII via reaction of step (c′) by hydrogenation of double bonds. Thereaction can be carried out by using catalyst for example Pd-C, platinummetal or its oxide and the like. Any of the conditions conventional insuch hydrogenation reactions can be utilized to carry out the reactionof step (c′).

The compound of formula XLII can be converted to the compound of formulaXLIII via reaction of step (d′) by reducing acid to alcohol. Thereaction can be carried out utilizing a conventional reducing agent forexample alkali metal hydride such as lithium aluminum hydride. Thereaction can be carried out in a suitable solvent, such astetrahydrofuran. Any of the conditions conventional in such reductionreactions can be utiezed to carry out the reaction of step (d′).

The compound of formula XLIII can be converted to the compound offormula XXXVII by displacing alcohol with bromo by treating the compoundof formula XLIII with bromine, phosphorus tribromide, carbontetrabromide and the like. Any conventional method to displace alcoholwith bromo can be utilized to carry out the reaction of step (e′).

The compound of formula XVII where R³ is hydrogen, halo, alkoxy havingfrom 1 to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms, i.e.compounds of formula:

can be prepared via reaction of scheme 8.

In the reaction scheme of Scheme 8, R⁴ is alkyl group having from 1 to 2carbon atoms, and P is a protecting group.

The compound of formula XXV can be converted to the compound of formulaXLIV via the reaction of step (f′) by protecting the hydroxy group andthen deprotecting the ester group by utilizing suitable protecting anddeprotecting groups such as those described in Protecting Groups inOrganic Synthesis by T. Greene.

The compound of formula XLIV can be converted to the compound of formulaXLV via reaction of step (g′) by reducing acid to alcohol. The reactioncan be carried out utilizing a conventional reducing agent for examplealkali metal hydride such as lithium aluminum hydride. The reaction canbe carried out in a suitable solvent, such as tetrahydrofuran. Any ofthe conditions conventional in such reduction reactions can be utilizedto carry out the reaction of step (g′).

The compound of formula XLV can be converted to the compound of formulaXLVI via reaction of step (h′) by oxidation of alcohol to the aldehyde.The reaction can be carried out utilizing a suitable oxidizing agent forexample pyridinium chlorochromate, dimethyl sulfoxide activated by2,4,6-trichloro[1,3,5]-triazine (cyanuric chloride, TCIT) under Swernoxidation conditions (J.O.C. 2001, 66, 7907-7909) and the like. Any ofthe conditions conventional in such oxidation reactions can be utilizedto carry out the reaction of step (h′).

In the compound of formula XLVI, the hydroxy group can be deprotectedvia reaction of step (i′) by utilizing suitable deprotecting groups suchas those described in Protecting Groups in Organic Synthesis by T.Greene to give the compound of formula XVII.

The compound of formula XL, where R⁴ is alkyl group having from 1 to 2carbon atoms and k is 1 to 2, i.e. compounds of formula:Ph₃P⁺—(CH₂)_(k)—CO₂R⁴}Br⁻can be prepared via reaction of scheme 9.

In the reaction scheme of Scheme 9, R⁴ and k are as above.

The compound of formula XLVII can be reacted with the compound offormula XLVIII via the reaction of step (j′) to give compound of formulaXL. Any of the conditions conventionally used in reactingtriphenylphosphine with hydrohalide can be utilized to carry out thereaction of step (j′).

The compound of formula III,A(CH₂)_(t+n)—OHand the compound of formula IV, where t is 0 or 1, n is 1 or 2, i.e.compounds of formula:A(CH₂)_(t+n)—Ywherein A is described as above, and Y is a leaving group, can beprepared via reaction of scheme 10.

In the reaction of Scheme 10, A is described as above and Y is a leavinggroup.

The compound of formula XLIX can be reduced to the compound of formula Lvia reaction of step (k′). The reaction is carried out utilizing aconventional reducing agent for example alkali metal hydride such aslithium aluminum hydride. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran. Any of the conditions conventional insuch reduction reactions can be utilized to carry out the reaction ofstep (k′).

The compound of formula L is the compound of formula III where t is 0and n is 1.

The compound of formula L can be converted to the compound of formula LIby displacing hydroxyl group with a halogen preferred halogen beingbromo or chloro. Appropriate halogenating reagents include but are notlimited to thionyl chloride, bromine, phosphorous tribromide, carbontetrabrornide and the like. Any conditions conventional in suchhalogenation reactions can be utilized to carry out the reaction of step(l′).

The compound of formula LI is the compound of formula IV where t is 0and n is 1.

The compound of formula LI can be converted to the compound of formulaLII by reacting LI with an alkali metal cyanide for example sodium orpotassium cyanide. The reaction is carried out in a suitable solvent,such as dimethyl sulfoxide. Any of the conditions conventionally used inthe preparation of nitrile can be utilized to carry out the reaction ofstep (m′).

The compound of formula LII can be converted to the compound of formulaLIII via reaction of step (n′) by acid or base hydrolysis. In carryingout this reaction it is generally preferred to utilize basic hydrolysis,for example aqueous sodium hydroxide. Any of the conditionsconventionally used in hydrolysis of nitrile can be utilized to carryout the reaction of step (n′).

The compound of formula LIII can be reduced to give the compound offormula LIV via reaction of step (o′). This reaction can be carried outin the same manner as described hereinbefore in the reaction of step(k′).

The compound of formula LIV is the compound of formula III where t is 1and n is 1.

The compound of formula LIV can be converted to the compound of formulaLV via reaction of step (p′) in the same manner as describedhereinbefore in connection with the reaction of step (l′).

The compound of formula LV is the compound of formula IV where t is 1and n is 1.

The compound of formula LV can be reacted with diethyl malonateutilizing a suitable base for example sodium hydride to give compound offormula LVI. The reaction is carried out in suitable solvents, such asdimethylformamide, tetrahydrofuran and the like. Any of the conditionsconventional in such alkylation reactions can be utilized to carry outthe reaction of step (q′).

The compound of formula LVI can be hydrolyzed by acid or base to givecompound of formula LVII via reaction of step (r′).

The compound of formula LVII can be converted to the compound of formulaLVIII via reaction of step (s′) in the same manner as describedhereinbefore in connection with the reaction of step (k′).

The compound of formula LVIII is the compound of formula III where t is1 and n is 2.

The compound of formula LVIII can be converted to the compound offormula LIX via reaction of step (t′) in the same manner as describedhereinbefore in connection with the reaction of step (l′).

The compound of formula LIX is the compound of formula IV where t is 1and n is 2.

The compound of formula II where R³ is halo, alkoxy having from 1 to 3carbon atoms or alkyl having from 1 to 3 carbon atoms, i.e. compounds offormula:

can be prepared via reaction of scheme 11.

In the reaction of Scheme 11, R¹ is H and R³ is halo, alkoxy having from1 to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms. R⁴ isalkyl having from 1 to 2 carbon atoms.

The compound of formula XXV can be converted to the compound of formulaLX via reaction of step (u′) by ester hydrolysis.

The compound of formula II can be synthesized from the compound offormula LX via reaction of step (v′) by adapting the method of George MRubottom et al., J. Org. Chem. 1983, 48, 1550-1552.

The compound of formula LX where R¹ is H and R³ is halo, i.e. compoundsof formula:

are either commercially available or can be prepared according to themethods described in the literature as follows:

-   1. 3-Br or F-2-OHC₆H₃CO₂H-   Canadian Journal of Chemistry (2001), 79(11) 1541-1545.-   2. 4-Br-2-OHC₆H₃CO₂H-   WO 9916747 or JP 04154773.-   3. 2-Br-6-OHC₆H₃CO₂H-   JP 47039101.-   4. 2-Br-3-OHC₆H₃CO₂H-   WO 9628423.-   5. 4-Br-3-OHC₆H₃CO₂H-   WO 2001002388.-   6. 3-Br-5-OHC₆H₃CO₂H-   Journal of labelled Compounds and Radiopharmaceuticals (1992), 31    (3), 175-82.-   7. 2-Br-5-OHC₆H₃CO₂H and 3-Cl-4-OHC₆H₃CO_(2H)-   WO 9405153 and U.S. Pat. No. 5,519,133.-   8. 2-Br4OHC₆H₃CO₂H and 3-Br4OHC₆H₃CO₂H-   WO 20022018323-   9. 2-Cl-6-OHC₆H₃CO₂H-   JP 06293700-   10. 2-Cl-3-OHC₆H₃CO₂H-   Proceedings of the Indiana Academy of Science (1983), Volume date    1982,92, 145-51.-   11. 3-Cl-5-OHC₆H₃CO₂H-   WO 2002000633 and WO 2002044145.-   12. 2-Cl-5-OHC₆H₃CO₂H-   WO 9745400.-   13. 5-I-2-OHC₆H₃CO₂H and 3-I, 2-OHC₆H₃CO₂H-   Z. Chem. (1976), 16(8), 319-320.-   14. 4-I-2-OHC₆H₃CO₂H-   Journal of Chemical Research, Synopses (1994), (11), 405.-   15. 6-I-2-OHC₆H₃CO₂H-   U.S. Pat. No. 4,932,999.-   16. 2-I-3-OHC₆H₃CO₂H and 4-I-3-OHC₆H₃CO₂H-   WO 9912928.-   17. 5-I-3-OHC₆H₃CO₂H-   J. Med. Chem. (1973), 16(6), 684-7.-   18. 2-I-OHC₆H₃CO₂H-   Collection of Czechoslovak Chemical Communications, (1991), 56(2),    459-77.-   19. 3-I-4-OHC₆H₃CO₂,-   J.O.C. (1990), 55(18), 5287-91.

The compound of formula LX, where R¹ is H and R³ is alkoxy having from 1to 3 carbon atoms, i.e. compounds of formula:

can be synthesized via the reaction of scheme 12.

In the reaction of Scheme 12, R¹ and R³ are as above, and R⁴is alkylgroup having from 1 to 2 carbon atoms.

The compound of formula LXI can be converted to the compound of formulaLXII by reducing the aldehyde to primary alcohol. In carrying out thisreaction, it is preferred but not limited to use sodium borohydride asthe reducing reagent. Any of the conditions suitable in such reductionreactions can be utilized to carry out the reaction of step (w′).

The compound of formula LXII can be converted to the compound of formulaLXIII via reaction of step (x′) by protecting 1-3 Diols by using1,1,3,3-Tetraisopropyldisiloxane. The suitable conditions for thisprotecting group can be described in the Protecting Groups in OrganicSynthesis by T. Greene.

The compound of formula LXIII can be converted to the compound offormula LXIV via reaction of step (y′) by protecting the phenol groupusing benzyl bromide. The suitable conditions for this protecting groupcan be described in the Protecting Groups in Organic Synthesis by T.Greene.

The compound of formula LXIV can be converted to the compound of formulaLXV by deprotection using tetrabutylammonium fluoride via reaction ofstep (z′). The suitable conditions for the deprotection can be describedin the Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula LXV can be converted to compound of formula LXVIvia reaction of step (a″) by oxidation. Any conventional oxidizing groupthat converts primary alcohol to an acid for example chromium oxide andthe like can be utiliz to carry out the reaction of step (a″).

The compound of formula LXVI can be converted to the compound of formulaLXVII by esterification of compound of formula LXVI with methanol orethanol. The reaction can be carried out either by using catalysts forexample H₂SO₄, TsOH and the like or by using dehydrating agents forexample dicyclohexylcarbodiimide and the like. Any of the conditionsconventional in such esterification reactions can be utilized to carryout the reaction of step (b″).

The compound of formula LXVII can be converted to the compound offormula LXVIII by etherifying or alkylating the compound of formulaLXVII with methyl halide or ethyl halide or propyl halide by usingsuitable base for example potassium carbonate, sodium hydride and thelike. The reaction is carried out in conventional solvents, such astetrahydrofuran, dimethylformamide. The reaction is generally carriedout at temperatures of from 0° C. to 40° C. Any of the conditionssuitable in such alkylation reactions can be utilized to carry out thereaction of step (c″).

The compound of formula LXVIII can be converted to the compound offormula LXIX via reaction of step (d″) by deprotection of ester andbenzyl groups. The suitable deprotecting conditions can be described inthe Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula LX, where R¹ is H and R³ is alkoxy having from 1to 3 carbon atoms, i.e. compounds of formula:

are either commercially available or can be prepared according to themethods described in the literature as follows:

-   1. 2-OMe-4-OHC₆H₃CO₂H-   US 2001034343 or WO 9725992.-   2. 5-OMe-3-OHC₆H₃CO₂H-   J.O.C (2001), 66(23), 7883-88.-   3. 2-OMe-5-OHC₆H₃CO₂H-   U.S. Pat. No. 6,194,406 (Page 96) and Journal of the American    Chemical Society (1985), 107(8), 2571-3.-   4. 3-OEt-5-OHC₆H₃CO₂H-   Taiwan Kexue (1996), 49(1), 51-56.-   5. 4-OEt-3-OHC₆H₃CO₂H-   WO 9626176-   6. 2-OEt-4-OHC₆H₃CO₂H-   Takeda Kenkyusho Nempo (1965), 24,221-8.-   JP 07070025.-   7. 3-OEt-4-OHC₆H₃CO₂H-   WO 9626176.-   8. 3-OPr-2-OHC₆H₃CO₂H-   JP 07206658, DE 2749518.-   9. 4-OPr-2-OHC₆H₃CO₂H-   Farmacia (Bucharest) (1970), 18(8), 461-6.-   JP 08119959.-   10. 2-OPr-5-OHC₆H₃CO₂H and 2-OEt-5-OHC₆H₃CO₂H-   Adapt synthesis from U.S. Pat. No. 6,194,406 (Page 96) by using    propyl iodide and ethyl iodide.-   11. 4-OPr-3-OHC₆H₃CO₂H-   Adapt synthesis from WO 9626176-   12. 2-OPr-4-OHC₆H₃CO₂H-   Adapt synthesis from Takeda Kenkyusho Nempo (1965), 24,221-8 by    using propyl halide.-   13. 4-OEt-3-OHC₆H₃CO₂H-   Biomedical Mass Spectrometry (1985), 12(4), 163-9.-   14. 3-OPr-5-OHC₆H₃CO₂H

Adapt synthesis from Taiwan Kexue (1996), 49(1), 51-56 by using propylhalide. The compound of formula LX, where R¹ is H and R³ is an alkylhaving from 1 to 3 carbon atoms, i.e. compounds of formula:

are either commercially available or can be prepared according to themethods described in the literature as follows:

-   1. 5-Me-3-OHC₆H₃CO₂H and 2-Me-5-OHC₆H₃CO₂H-   WO 9619437.-   J.O.C. 2001, 66, 7883-88.-   2. 2-Me-4-OHC₆H₃CO₂H-   WO 8503701.-   3. 3-Et-2-OHC₆H₃CO₂H and 5-Et-2-OHC₆H₃CO₂H-   J. Med. Chem. (1971), 14(3), 265.-   4. 4-Et-2-OHC₆H₃CO₂H-   Yaoxue Xuebao (1998), 33(1), 67-71.-   5. 2-Et-6-OHC₆H₃CO₂H and 2-n-Pr-6-OHC₆H₃CO₂H-   J. Chem. Soc., Perkin Trans 1 (1979), (8), 2069-78.-   6. 2-Et-3-OHC₆H₃CO₂H-   JP 10087489 and WO 9628423.-   7. 4-Et-3-OHC₆H₃CO₂H-   J.O.C. 2001, 66, 7883-88.-   WO 9504046.-   8. 2-Et-5-OHC₆H₃CO₂H-   J.A.C.S (1974), 96(7), 2121-9.-   9. 2-Et-4-OHC₆H₃CO₂H and 3-Et-4-OHC₆H₃CO₂H-   JP 04282345.-   10. 3-n-Pr-2-OHC₆H₃CO₂H-   J.O.C (1991), 56(14), 4525-29.-   11. 4-n-Pr-2-OHC₆H₃CO₂H-   EP 279630.-   12. 5-n-Pr-2-OHC₆H₃CO₂H-   J. Med. Chem (1981), 24(10), 1245-49.-   13. 2-n-Pr-3-OHC₆H₃CO₂H-   WO 9509843 and WO 9628423.-   14. 4-n-Pr-3-OHC₆H₃CO₂H-   WO 9504046.-   15. 2-n-Pr-5-OHC₆H₃CO₂H-   Synthesis can be adapted from J.A.C.S (1974), 96(7), 2121-9 by using    ethyl alpha formylvalerate.-   16. 3-n-Pr-4-OHC₆H₃CO₂H-   Polymer (1991), 32(11) 2096-105.-   17. 2-n-Pr-4-OHC₆H₃CO₂H-   3-Propylphenol can be methylated to 3-Propylanisole, which was then    formylated to 4-Methoxy-3-benzaldehyde. The aldehyde can be oxidized    by Jone's reagent to give corresponding acid and deprotection of    methyl group by BBr₃ will give the title compound.-   18. 1. 3-Et-5-OHC₆H₃CO₂H and 3-Pr-n-5-OHC₆H₃CO₂H-   Adapt synthesis from J.O.C. 2001, 66,7883-88 by using    2-Ethylacrolein and 2-Propylacrolein.

USE IN METHODS OF TREATMENT

This invention provides a method for treating a mammalian subject with acondition selected from the group consisting of insulin resistancesyndrome and diabetes (both primary essential diabetes such as Type IDiabetes or Type II Diabetes and secondary nonessential diabetes),comprising administering to the subject an amount of a biologicallyactive agent as described herein effective to treat the condition. Inaccordance with the method of this invention a symptom of diabetes orthe chance of developing a symptom of diabetes, such as atherosclerosis,obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy,neuropathy, retinopathy, foot ulceration and cataracts, each suchsymptom being associated with diabetes, can be reduced. This inventionalso provides a method for treating hyperlipidemia comprisingadministering to the subject an amount of a biologically active agent asdescribed herein effective to treat the condition. As shown in theExamples, compounds reduce serum triglycerides and free fatty acids inhyperlipidemic animals. This invention also provides a method fortreating cachexia comprising administering to the subject an amount of abiologically active agent as described herein effective to treat thecachexia. This invention also provides a method for treating obesitycomprising administering to the subject an amount of a biologicallyactive agent as described herein effective to treat the condition. Thisinvention also provides a method for treating a condition selected fromatherosclerosis or arteriosclerosis comprising administering to thesubject an amount of a biologically active agent as described hereineffective to treat the condition. The active agents of this inventionare effective to treat hyperlipidemia, fatty liver disease, cachexia,obesity, atherosclerosis or arteriosclerosis whether or not the subjecthas diabetes or insulin resistance syndrome. The agent can beadministered by any conventional route of systemic administration.Preferably the agent is administered orally. Accordingly, it ispreferred for the medicament to be formulated for oral administration.Other routes of administration that can be used in accordance with thisinvention include rectally, parenterally, by injection (e.g.intravenous, subcutaneous, intramuscular or intraperitioneal injection),or nasally.

Further embodiments of each of the uses and methods of treatment of thisinvention comprise administering any one of the embodiments of thebiologically active agents described above. In the interest of avoidingunnecessary redundancy, each such agent and group of agents is not beingrepeated, but they are incorporated into this description of uses andmethods of treatment as if they were repeated.

Many of the diseases or disorders that are addressed by the compounds ofthe invention fall into two broad categories: Insulin resistancesyndromes and consequences of chronic hyperglycemia. Dysregulation offuel metabolism, especially insulin resistance, which can occur in theabsence of diabetes (persistent hyperglycemia) per se, is associatedwith a variety of symptoms, including hyperlipidemia, atherosclerosis,obesity, essential hypertension, fatty liver disease (NASH; nonalcoholicsteatohepatitis), and, especially in the context of cancer or systemicinflammatory disease, cachexia. Cachexia can also occur in the contextof Type I Diabetes or late-stage Type II Diabetes. By improving tissuefuel metabolism, active agents of the invention are useful forpreventing or amelioriating diseases and symptoms associated withinsulin resistance, as is demonstrated in animals in the Examples. Whilea cluster of signs and symptoms associated with insulin resistance maycoexist in an individual patient, it many cases only one symptom maydominate, due to individual differences in vulnerability of the manyphysiological systems affected by insulin resistance. Nonetheless, sinceinsulin resistance is a major contributor to many disease conditions,drugs which address this cellular and molecular defect are useful forprevention or amelioration of virtually any symptom in any organ systemthat may be due to, or exacerbated by, insulin resistance.

When insulin resistance and concurrent inadequate insulin production bypancreatic islets are sufficiently severe, chronic hyperglycemia occurs,defming the onset of Type II diabetes mellitus (NIDDM). In addition tothe metabolic disorders related to insulin resistance indicated above,disease symptoms secondary to hyperglycemia also occur in patients withNIDDM. These include nephropathy, peripheral neuropathy, retinopathy,microvascular disease, ulceration of the extremities, and consequencesof nonenzymatic glycosylation of proteins, e.g. damage to collagen andother connective tissues.

Attenuation of hyperglycemia reduces the rate of onset and severity ofthese consequences of diabetes. Because, as is demonstrated in theExamples, active agents and compositions of the invention help to reducehyperglycemia in diabetes, they are useful for prevention andamelioration of complications of chronic hyperglycemia.

Both human and non-human mammalian subjects can be treated in accordancewith the treatment method of this invention. The optimal dose of aparticular active agent of the invention for a particular subject can bedetermined in the clinical setting by a skilled clinician. In the caseof oral administration to a human for treatment of disorders related toinsulin resistance, diabetes, hyperlipidemia, fatty liver disease,cachexia or obesity the agent is generally administered in a daily doseof from 1 mg to 400 mg, administered once or twice per day. In the caseof oral administration to a mouse the agent is generally administered ina daily dose from 1 to 300 mg of the agent per kilogram of body weightActive agents of the invention are used as monotherapy in diabetes orinsulin resistance syndrome, or in combination with one or more otherdrugs with utility in these types of diseases, e.g. insulin releasingagents, prandial insulin releasers, biguanides, or insulin itself. Suchadditional drugs are administered in accord with standard clinicalpractice. In some cases, agents of the invention will improve theefficacy of other classes of drugs, permitting lower (and therefore lesstoxic) doses of such agents to be administered to patients withsatisfactory therapeutic results.

Established safe and effective dose ranges in humans for representativecompounds are: metformin 500 to 2550 mg/day; glyburide 1.25 to 20mg/day; GLUCOVANCE (combined formulation of metformin and glyburide)1.25 to 20 mg/day glyburide and 250 to 2000 mg/day metformin;atorvastatin 10 to 80 mg/day; lovastatin 10 to 80 mg/day; pravastatin 10to 40 mg/day; and simvastatin 5-80 mg/day; clofibrate 2000 mg/day;gemfibrozil 1200 to 2400 mg/day, rosiglitazone 4 to 8 mg/day;pioglitazone 15 to 45 mg/day; acarbose 75-300 mg/day; repaglinide 0.5 to16 mg/day.

Type I Diabetes Mellitus: A patient with Type I diabetes manages theirdisease primarily by self-administration of one to several doses ofinsulin per day, with frequent monitoring blood glucose to permitappropriate adjustment of the dose and timing of insulin administration.Chronic hyperglycemia leads to complications such as nephropathy,neuropathy, retinopathy, foot ulceration, and early mortality;hypoglycemia due to excessive insulin dosing can cause cognitivedysfumction or unconsciousness. A patient with Type I diabetes istreated with 1 to 400 mg/day of an active agent of this invention, intablet or capsule form either as a single or a divided dose. Theanticipated effect will be a reduction in the dose or frequency ofadministration of insulin required to maintain blood glucose in asatisfactory range, and a reduced incidence and severity of hypoglycemicepisodes. Clinical outcome is monitored by measurement of blood glucoseand glycosylated hemoglobin (an index of adequacy of glycemic controlintegrated over a period of several months), as well as by reducedincidence and severity of typical complications of diabetes. Abiologically active agent of this invention can be administered inconjunction with islet transplantation to help maintain theanti-diabetic efficacy of the islet transplant.

Type II Diabetes Mellitus: A typical patient with Type II diabetes(NIDDM) manages their disease by programs of diet and exercise as wellas by taking medications such as metformin, glyburide, repaglinide,rosiglitazone, or acarbose, all of which provide some improvement inglycemic control in some patients, but none of which are free of sideeffects or eventual treatment failure due to disease progression. Isletfailure occurs over time in patients with NIDDM, necessitating insulininjections in a large fraction of patients. It is anticipated that dailytreatment with an active agent of the invention (with or withoutadditional classes of antidiabetic medication) will improve glycemiccontrol, reduce the rate of islet failure, and reduce the incidence andseverity of typical symptoms of diabetes. In addition, active agents ofthe invention will reduce elevated serum triglycerides and fatty acids,thereby reducing the risk of cardiovascular disease, a major cause ofdeath of diabetic patients. As is the case for all other therapeuticagents for diabetes, dose optimization is done in individual patientsaccording to need, clinical effect, and susceptibility to side effects.

Hyperlipidemia: Elevated triglyceride and free fatty acid levels inblood affect a substantial fraction of the population and are animportant risk factor for atherosclerosis and myocardial infarction.Active agents of the invention are useful for reducing circulatingtriglycerides and free fatty acids in hyperlipidemic patients.Hyperlipidemic patients often also have elevated blood cholesterollevels, which also increase the risk of cardiovascular disease.Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors(“statins”) can be administered to hyperlipidemic patients in additionto agents of the invention, optionally incorporated into the samepharmaceutical composition.

Fatty Liver Disease: A substantial fraction of the population isaffected by fatty liver disease, also known as nonalcoholicsteatohepatitis (NASH); NASH is often associated with obesity anddiabetes. Hepatic steatosis, the presence of droplets of triglycerideswith hepatocytes, predisposes the liver to chronic inflammation(detected in biopsy samples as infiltration of inflammatory leukocytes),which can lead to fibrosis and cirrhosis. Fatty liver disease isgenerally detected by observation of elevated serum levels ofliver-specific enzymes such as the transaminases ALT and AST, whichserve as indices of hepatocyte injury, as well as by presentation ofsymptoms which include fatigue and pain in the region of the liver,though definitive diagnosis often requires a biopsy. The anticipatedbenefit is a reduction in liver inflammation and fat content, resultingin attenuation, halting, or reversal of the progression of NASH towardfibrosis and cirrhosis.

Pharmaceutical Compositions

This invention provides a pharmaceutical composition comprising abiologically active agent as described herein and a pharmaceuticallyacceptable carrier. Further embodiments of the pharmaceuticalcomposition of this invention comprise any one of the embodiments of thebiologically active agents described above. In the interest of avoidingunnecessary redundancy, each such agent and group of agents is not beingrepeated, but they are incorporated into this description ofpharmaceutical compositions as if they were repeated.

Preferably the composition is adapted for oral administration, e.g. inthe form of a tablet, coated tablet, dragee, hard or soft gelatincapsule, solution, emulsion or suspension. In general the oralcomposition will comprise from 1 mg to 400 mg of such agent. It isconvenient for the subject to swallow one or two tablets, coatedtablets, dragees, or gelatin capsules per day. However the compositioncan also be adapted for administration by any other conventional meansof systemic administration including rectally, e.g. in the form ofsuppositories, parenterally, e.g. in the form of injection solutions, ornasally.

The biologically active compounds can be processed with pharmaceuticallyinert, inorganic or organic carriers for the production ofpharmaceutical compositions. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragees and hardgelatin capsules. Suitable carriers for soft gelatin capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active ingredient no carriersare, however, usually required in the case of soft gelatin capsules,other than the soft gelatin itself. Suitable carriers for the productionof solutions and syrups are, for example, water, polyols, glycerol,vegetable oils and the like. Suitable carriers for suppositories are,for example, natural or hardened oils, waxes, fats, semil-liquid orliquid polyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,coating agents or antioxidants. They can also contain still othertherapeutically valuable substances, particularly antidiabetic orhypolipidemic agents that act through mechanisms other than thoseunderlying the effects of the compounds of the invention. Agents whichcan advantageously be combined with compounds of the invention in asingle formulation include but are not limited to biguanides such asmetformin, insulin releasing agents such as the sulfonylurea insulinreleaser glyburide and other sulfonylurea insulin releasers,cholesterol-lowering drugs such as the “statin” HMG-CoA reductaseinhibitors such as atrovastatin, lovastatin, pravastatin andsimvastatin, PPAR-alpha agonists such as clofibrate and gemfibrozil,PPAR-gamma agonists such as thiazolidinediones (e.g. rosiglitazone andpioglitazone, alpha-glucosidase inhibitors such as acarbose (whichinhibit starch digestion), and prandial insulin releasers such asrepaglinide. The amounts of complementary agents combined with compoundsof the invention in single formulations are in accord with the dosesused in standard clinical practice. Established safe and effective doseranges for certain representative compounds are set forth above.

The invention will be better understood by reference to the followingexamples which illustrate but do not limit the invention describedherein.

CHEMICAL SYNTHESIS EXAMPLES Example 1(3-(2,6-Dimethylbenzyloxy)-phenyl)-oxoacetic acid

Step A: Preparation of (3-(2,6-Dimethylbenzyloxy)-phenyl)-oxoaceticacid:

To a stirred solution of 1-(3-(2,6-Dimethylbenzyloxy)-phenyl)-ethanone(WO 02/100341, 5 g, 20 mmol) in pyridine (20 ml) was added seleniumdioxide (3.492 g, 31 mmol) diluted in pyridine (20 ml). The reactionmixture was heated at 100° C. for 3 hours, decanted from selenium metaland concentrated in vacuo to give orange oil, which solidified at roomtemperature. The solid was dissolved in saturated NaHCO₃ (40 ml) andstirred with decolorizing carbon (0.5 g) for an hour at roomtemperature. The reaction mixture was filtered through celite andaqueous filtrate was acidified using 6N HCI (6 ml). A gray precipitant(6.3 g) was filtered and dried in vacuo at 40° C. for 2 hours. Theacidified filtrate was washed with ether (2×75 ml), dried over Na₂SO₄,filtered, and concentrated to yield a white solid (0.5 g).Recrystallization using carbon tetrachloride afforded 4.9 g of the titlecompound with pyridine as an impurity. The semipure material (4.2 g) wasdissolved in ethyl acetate (150 ml) and washed with 5% HCl (2×50 ml).The organic layer was dried over Na₂SO₄, filtered and concentrated toyield a yellow solid (3.9 g). The solid was recrystallized with carbontetrachloride (30 ml) to afford the title compound (3.03 g) as a lightyellow solid.

¹H NMR (DMSO): 2.3 (s, 6H); 5.1 (s, 2H); 7.1 (m, 2H); 7.2 (m, 2H); 7.4(m, 1H); 7.6 (m, 2H).

BIOLOGICAL ACTIVITY EXAMPLES

For all of the biological activity examples that follow, Compound CQ wasproduced in accordance with chemical synthesis example 1.

Example 2 Antidiabetic Effects of Compounds of the Invention in db/dbMice

C57BL/Ksola (db/db) mice have a defect in leptin signaling, leading tohyperphagia, obesity and diabetes. Moreover, unlike ob/ob mice on aC57BL/6J background, db/db mice on a C57BLKS background undergo failureof their insulin-producing pancreatic islet cells, resulting inprogression from hyperinsulinemia (associated with peripheral insulinresistance) to hypoinsulinemic diabetes.

Male obese (db/db homozygote) C57BL/Ksola mice approximately 8 weeks ofage, were obtained from Jackson Labs (Bar Harbor, Me.) and sorted intogroups of 7 animals each animals such that the body weights (40-45 g)and serum glucose levels (≧300 mg/dl in fed state) were similar betweengroups. A minimum of 7 days was allowed for adaptation after arrival.All animals were maintained under controlled temperature (23° C.),relative humidity (50±5%) and light (7:00-19:00), and allowed freeaccess to standard chow (Formulab Diet 5008, Quality Lab Products,Elkridge, Md.) and water.

Treatment cohorts were given daily oral doses of vehicle (1%hydroxypropylmethylcellulose), Compounds BI, CF, CG, CQ or phenylacetatefor 17 days. At the end of the treatment period, blood samples werecollected and serum glucose and triglycerides were measured. Astatistically significant reduction in blood glucose or triglyceridesversus animals treated with oral vehicle is considered a positivescreening result for a drug. TABLE I The effects of Compounds BI, CF,CG, CQ and phenylacetate in a db/db mouse model of type I diabetesTriglycerides Groups Glucose mg/dL (±SEM) (mg/dL) Vehicle (Control) 812± 34 352 ± 27 BI - 100 mg/kg 472 ± 54 116 ± 4  BI- 150 mg/kg 348 ± 67 90± 6 CF - 30 mg/kg 586 ± 31 156 ± 20 CF - 60 mg/kg 604 ± 36 120 ± 13 CF -100 mg/kg 391 ± 61 92 ± 6 CG - 100 mg/kg 753 ± 24 166 ± 14 CQ - 60 mg/kg691 ± 37 175 ± 25 CQ - 100 mg/kg 786 ± 65 125 ± 10 Phenylacetate - 300mg/kg 661 ± 64 171 ± 33*p < 0.05 significantly different compared with vehicle-control

1-5. (canceled)
 6. A method for treating a mammalian subject with acondition selected from the group consisting of insulin resistancesyndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia,obesity, atherosclerosis and arteriosclerosis comprising administeringto the subject an amount of a biologically active agent, wherein theagent is a compound of the formula:

wherein n is 1 or 2; m is 0 to 4; q is 0 or 1; t is 0 or 1; R² is alkylhaving from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkyl having from1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; A isphenyl, unsubstituted or substituted by 1 or 2 groups selected from:halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl having from 3 to6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one ortwo ring carbons are independently mono-substituted by methyl or ethyl;or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatomsselected from N, S and O and the heteroaromatic ring is covalently boundto the remainder of the compound of formula I by a ring carbon; and R¹is hydrogen or alkyl having 1 or 2 carbon atoms; or when R¹ is hydrogen,a pharmaceutically acceptable salt of the compound.
 7. The method ofclaim 6, wherein n is 1; q is 0; t is 0; R³ is hydrogen; and A isphenyl, unsubstituted or substituted by 1 or 2 groups selected from:halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy.
 8. The method of claim 7,wherein wherein A is 2,6-dimethylphenyl.
 9. The method of claim 8,wherein the biologically active agent is[3-(2,6-Dimethylbenzyloxy)-phenyl]-oxoacetic acid.
 10. The method ofclaim 6, wherein the subject is a human.
 11. The method of claim 10,wherein the agent is administered orally in an amount from one milligramto four hundred milligrams per day.
 12. The method of claim 6, whereinthe condition is insulin resistance syndrome or Type II Diabetes. 13.The method of claim 6, wherein the treatment reduces a symptom ofdiabetes or the chances of developing a symptom of diabetes, wherein thesymptom is selected from the group consisting of: atherosclerosis,obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy,neuropathy, retinopathy, foot ulceration and cataracts, associated withdiabetes.
 14. A pharmaceutical composition for use in the treatment of acondition selected from the group consisting of insulin resistancesyndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia,obesity, atherosclerosis, arteriosclerosis and adapted for oraladministration, comprising a pharmaceutically acceptable carrier andfrom one milligram to four hundred milligrams of a biologically activeagent, wherein the agent is a compound of the formula:

wherein n is 1 or 2; m is 0 to 4; q is 0 or 1; t is 0 or 1; R² is alkylhaving from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkyl having from1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; A isphenyl, unsubstituted or substituted by 1 or 2 groups selected from:halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl having from 3 to6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one ortwo ring carbons are independently mono-substituted by methyl or ethyl;or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatomsselected from N, S and O and the heteroaromatic ring is covalently boundto the remainder of the compound of formula I by a ring carbon; and R¹is hydrogen or alkyl having 1 or 2 carbon atoms; or when R¹ is hydrogen,a pharmaceutically acceptable salt of the compound.
 15. Thepharmaceutical composition of claim 14, wherein n is 1; q is 0; t is 0;R³ is hydrogen; and A is phenyl, unsubstituted or substituted by 1 or 2groups selected from: halo, alkyl having 1 or 2 carbon atoms,perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy.
 16. The pharmaceutical composition of claim 15,wherein wherein A is 2,6-dimethylphenyl.
 17. The pharmaceuticalcomposition of claim 16, wherein the biologically active agent is[3-(2,6-Dimethylbenzyloxy)-phenyl]-oxoacetic acid.
 18. Thepharmaceutical composition of claim 14 in oral dosage form.
 19. Abiologically active agent, wherein the agent is a compound of theformula:

wherein n is 1 or 2; m is 0 to 4; q is 0 or 1; t is 0 or 1; R² is alkylhaving from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkyl having from1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; A isphenyl, unsubstituted or substituted by 1 or 2 groups selected from:halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl having from 3 to6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one ortwo ring carbons are independently mono-substituted by methyl or ethyl;or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatomsselected from N, S and O and the heteroaromatic ring is covalently boundto the remainder of the compound of formula I by a ring carbon; and R¹is hydrogen or alkyl having 1 or 2 carbon atoms; or when R¹ is hydrogen,a pharmaceutically acceptable salt of the compound.
 20. The biologicallyactive agent of claim 19, wherein n is 1; q is 0; t is 0; R³ ishydrogen; and A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy.
 21. Thebiologically active agent of claim 19, wherein wherein A is2,6-dimethylphenyl.
 22. The biologically active agent of claim 21,[3-(2,6-Dimethylbenzyloxy)-phenyl]-oxoacetic acid.
 23. (canceled)